Upregulated FoxO1 promotes arrhythmogenesis in mice with heart failure and preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is a growing health problem, especially among older adults. In this condition, the heart’s pumping ability is normal, but the heart muscle becomes stiff and cannot relax properly between beats. This leads to shortness of breath, fatigue, and swelling. HFpEF is also associated with abnormal heart rhythms (arrhythmias), which can be dangerous or even life-threatening. Unfortunately, there are currently few effective treatments, in part because scientists still do not fully understand the root causes of HFpEF. One key feature of HFpEF is the buildup of scar tissue (called fibrosis) in the heart. This fibrosis makes the heart stiffer and contributes to both heart dysfunction and arrhythmias. Our research set out to understand why fibrosis happens in HFpEF and how it might be reversed. Using advanced genetic analysis, we studied heart tissue from mice with HFpEF and discovered something surprising: a gene called Forkhead Box O1 (FoxO1) was much more active than normal. FoxO1 plays many roles in the body, but in this case, it seemed to be involved in harmful processes that worsen heart function. We tested what would happen if we turned down FoxO1 activity in experimental models of HFpEF. The results were exciting. First, we found that blocking FoxO1 helped heart muscle cells (cardiomyocytes) and the cells that make scar tissue (fibroblasts) communicate more normally. This change reduced the amount of fibrosis and helped the heart muscle relax better between beats. Even more importantly, hearts with reduced FoxO1 activity had fewer abnormal rhythms, suggesting that this strategy could prevent some of the dangerous complications of HFpEF. We also took a closer look at the fibroblasts themselves, which are the main producers of scar tissue. When we specifically targeted FoxO1 in these cells, fibrosis decreased dramatically. As a result, the heart worked better and was less prone to arrhythmias. This research reveals that FoxO1 is a key player in driving both fibrosis and electrical instability in HFpEF. By targeting FoxO1, we can improve heart function and potentially prevent dangerous arrhythmias. These findings open the door to new treatment strategies for HFpEF—ones that go beyond just managing symptoms to actually correcting the underlying problems in the heart. In summary, our study not only identifies a new culprit (FoxO1) in the development of heart stiffness and arrhythmias but also shows that these harmful changes can be reversed. With further research, this discovery may lead to the development of new medications that improve the lives of people living with HFpEF by targeting the disease at its roots.